I have long had a deep and consistent commitment to an academic research career. My research experience has concentrated on globin gene regulation while my medical background includes 4 years of intensive clinical training in internal medicine and hematology. Areas to be developed by this program include basic science knowledge, ability to set research priorities and assess feasibility, ability to obtain funding and administer a lab and the ability to rigorously address questions of specific clinical import. Chromatin structure is one approach to the clinical problem of globin regulation in sickle cell disease and beta thalassemia. Many current techniques are not suitable for higher organisms. Yeast offers an altenative, genetically manipulable, system that can be explored while new approaches to the mammalian system are developed. A new technique, two dimensional hybridization mapping of chromatin will be used to detect important structural yeast proteins, such as HMGs and sequence specific binding proteins. Regulated genes will be studied in both active and inactive forms beginning with the Tyl repetative element and progressing to single copy genes. Regulation mutants, revertants and growth defective (CDC) mutants will be studied. Restriction endonuclease digestion of chromatin will be explored. Eventually these techniques will be brought to bear on globin regulation in mammalian systems. Development of research skills will be in 3 phases. The first is an intense basic science experience in the lab of Dr. Varshavsky at MIT. I will concentrate on designing and performing experiments, writing papers and broadening my scientific base. Clinical contact will be maintained through a weekly clinic involving less than 10% effort. The second phase will be a transition from supervised work toward independence. The interaction with both Drs. Varshavsky and Nathan should help balance clinical applications and scientific rigor. The final phase is as an independent investigator exploring the mammalian fetal to adult globin switch with rigorous chromatin technology.